1. AGING Young worm Old worm

2. Mutants in daf-2 are long lived Mutants in daf-2 are long lived daf-2 encodes an insulin/IGF-1 receptor homolog

3. daf-2 N2 daf-16 Fraction alive daf-16;daf-2 In order for daf-2 mutants to live long, they need daf-16 activity. DAF-16 is a forkhead-family transcription factor

4. daf-16 activity is required for the long lifespans of daf-2 mutants lifespans of daf-2 mutants Model: In the wild type, DAF-2 turns off DAF-16, preventing DAF-16 from extending lifespan preventing DAF-16 from extending lifespan

5. daf-2 Encodes a Hormone Receptor 35% aa identity to: Human Insulin Receptor IGF-1 Receptor Insulin Related Receptor Kimura et al., 1997

7. daf-2 OFF

8. P P P P -2 DAF -DAF- 16 a PI(4,5)P2 PI(3,4,5)P3 a a PDK-1 AKT-1 AKT-2 DAF- 18 PTEN AGE-1 PI 3K The DAF-2 pathway controls a second signal or hormone Downstream hormone

9. Model

10. YeastWormsFliesMice Stationary Phase Glucose Sensory Signals? Normal Conditions Pituitary Gland Growth Hormone IGF-1? IGF-1 Receptor? Other Insulin/ IGF-1 Pathways? LongevityLongevityLongevityLongevity Insulin/IGF-1Receptor Insulin/IGF-1? Chico (IRS) JuvenileHormone Insulin/IGF-1 DAF-2 Receptor AKT-1 DAF-16 Downstream Signal SIR-2 ? ? PKA PKAPathway Sir2 NAD Sch9 From Kenyon, Cell, April 20, 2001.

11. Decreasing signaling activity Extends lifespan Increases stress resistance Increases production of food storage substances Can inhibit reproduction This system probably arose early in evolution to allow animals to outlive unfavorable conditions, postponing reproduction until conditions improve. Lifespan extension can be uncoupled from infertility, changes in food utilization pathways, and stress resistance.

12. Model daf-16daf-2 LONGEVITYLONGEVITY Sensoryneurons